BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis.

Yi Chu Liao, Yung Song Wang, Yuh Cherng Guo, Kouichi Ozaki, Toshihiro Tanaka, Hsiu Fen Lin, Ming Hong Chang, Ku Chung Chen, Ming Lung Yu, Sheng Hsiung Sheu, Suh Hang Hank Juo

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Abstract

The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-κB (NF-κB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IκBβ and IKKβ. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-κB nuclear translocation.

Original languageEnglish
Pages (from-to)1065-1074
Number of pages10
JournalMolecular Medicine
Volume17
Issue number9-10
Publication statusPublished - Sep 2011
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Liao, Y. C., Wang, Y. S., Guo, Y. C., Ozaki, K., Tanaka, T., Lin, H. F., Chang, M. H., Chen, K. C., Yu, M. L., Sheu, S. H., & Juo, S. H. H. (2011). BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis. Molecular Medicine, 17(9-10), 1065-1074.